UDN Diagnostic Center of Excellence at Baylor College of Medicine - This is a continuation application for the Baylor College of Medicine (BCM) Diagnostic Center of Excellence (DCoE) of the Undiagnosed Diseases Network (UDN). In phase I and II of the UDN, we provided patients with undiagnosed diseases (UDD) access to state-of-the-art diagnostic methods, accelerated discovery of new biological mechanisms linking genetic variants with disease causation, identified potential treatment approaches, and engaged with the UDN and broader community to share best practices and innovations. We led all extramural (non NIH UDP) sites in combined acceptances and completion metrics, achieving 100% target for completing phase II evaluations (one of four extramural sites to do so). Of the cases completed to date (clinical and molecular analyses in phase I, II and phase III bridge year), we have achieved a 38.4% solve rate with an additional 11.4% with strong candidates. We have implemented innovative technologies like RNA sequencing- “first” directed genomic analysis on both whole blood and fibroblasts to complement exome and genome sequencing. This RNAseq-first analytical approach is now widely used in the broader community. In the current bridge phase III year, we have established collaboration with other NIH (NCATS Project GIVE, NHGRI Texome, and All of Us Evenings with Genetics Scholars) and community health programs (Texas Association of Community Health Clinics) to increase referral from all communities to our site. We achieved this by leveraging an integrated genetics program housed within the Department of Molecular and Human Genetics (DMHG). This includes a full spectrum of service, teaching, and research activities spanning from adult, pediatric, and prenatal care, to gene discovery and study of disease mechanisms to clinical trials, to a leading medical genetics diagnostic laboratory joint venture (Baylor Genetics), to community engagement via the DMHG Office of Community Engagement. Because all of these activities are subsumed under one organizational unit, we have been able to rapidly move discovery to practice, and also to serve as a nexus for the research community at BCM, the Texas Medical Center (TMC), and nationally. We propose to continue this remarkably integrated approach to discovery and care to achieve the objectives of the phase III UDN with 1) expansion of our hybrid-3rd party payor/research supported, tiered evaluations, 2) focus on recruitment from the broader community through collaboration with our NIH program/community partners, 3) efficiencies afforded by our virtual Consultagene platform, 4) application of ultra-low cost sequencing in partnership with Ultima Genomics to empower newer multi-omic analyses, and 5) data and resource sharing widely via the UDN DMCC. The leadership of the DMHG in the comprehensive practice of genetic medicine at BCM ensures the integration of the Depts. of Pediatrics, Medicine, and Neurology into the BCM UDN DCoE
